Rare Diseases Clinical Research Consortia (RDCRC) for the RDCR Network

尿素循环障碍（UCD）是一组罕见但具有破坏性的先天性代谢错误，从新生儿期到成年期具有高死亡率和发病率。UCD包括参与尿素生物合成的六种酶和两种膜转运蛋白中的任何一种缺乏：n -乙酰谷氨酸合成酶（NAGS）；氨甲酰磷酸合成酶I （CPSI）缺乏；鸟氨酸转氨基甲酰基酶缺乏症；精氨酸琥珀酸合成酶缺乏症（瓜氨酸血症）；精氨酸琥珀酸裂解酶（AL）缺乏（精氨酸琥珀酸尿症）；精氨酸酶缺乏症（Argininemia）；高鸟氨酸血症、高氨血症、高氮尿（HHH）综合征；和瓜氨酸血症II型。在之前的资助期间，我们在罕见病临床研究网络（RDCRN）内创建了尿素循环疾病联盟（UCDC），并成功启动了四个研究项目，旨在了解UCD的自然历史和开发新的治疗工具。目前，UCDC由8个美国站点组成，拥有一支由40多名研究人员和工作人员组成的跨学科团队。该联盟与国家尿素循环疾病基金会（尿素循环疾病的患者倡导组织）密切合作，并与工业界合作开发针对这些疾病的创新疗法。我们在此申请中提出3个完整的临床研究项目和一个试点项目。在临床项目中，我们将：1)继续我们的纵向研究，调查儿童和成人UCD的自然史、发病率、死亡率和生物标志物；2)开展n -氨甲酰谷氨酸的ii期/ ii期临床试验，评估其在使磷酸氨甲酰1和鸟氨酸氨甲酰转氨酶缺乏症患者的尿床正常化方面的疗效；和3)

Urea cycle disorders (UCD) are a group of 8 rare but devastating inborn errors of metabolism that carry a high mortality and morbidity from the newborn period through adulthood. UCD include deficiencies in any of the six enzymes and two membrane transporters involved in urea biosynthesis: N-acetylglutamate synthase (NAGS); Carbamyl phosphate synthase I (CPSI) deficiency; Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthase (AS) deficiency (Citrullinemia); Argininosuccinate lyase (AL) deficiency (Argininosuccinic aciduria); Arginase (ARG) deficiency (Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome; and Citrullinemia type II. During the previous grant period we have created the Urea Cycle Disorders Consortium (UCDC) within the Rare Diseases Clinical Research Network (RDCRN) and have launched successfully four research projects aimed at understanding the natural history of UCD and developing new tools for treatment. Currently the UCDC consists of 8 U.S. sites with an interdisciplinary team of over 40 investigators and staff. The consortium works closely with the National Urea Cycle Disorders Foundation, the patient advocacy organization for urea cycle disorders and has collaboration with industry to develop innovative therapies for these disorders. We propose in this application 3 full clinical research projects and a pilot project. In the clinical projects we will: 1) Continue our longitudinal study that investigates the natural history, morbidity, mortality and biomarkers in children and adults with UCD; 2) Perform a Phase ll/lll trial of N-carbamylglutamate to assess its efficacy in normalizing ureagenesis in patients with carbamyl phosphate 1 and ornithine transcarbamylase deficiencies; and 3) Assess neural mechanisms of injury in OTCD using structural MRI, functional MRI, and magnetic resonance spectroscopy. In the proposed initial pilot project we will study substrate availability for nitric oxide synthesis and associated pathogenesis in arginase and argininosuccinate lyase deficiencies. In addition to the research studies, we will expand and enhance our website for educational and research resources and continue to provide training and career development opportunities through the UCDC educational programs.